Proliferative cell disorders such as tumors and primary malignant tumors {herein, cancer(s)} in particular are problematic given their tendency to invade surrounding tissues and metastasize to distant organs in the body. To date the most frequently used methods for treating neoplasia, especially solid tumor forms of neoplasia, include surgical procedures, radiation therapy, drug chemotherapies, and combinations of the foregoing.
With over million cases of cancer being diagnosed annually, and cancer claiming more than half a million lives in the United States each year, there is increased need in new therapeutic modalities against such condition. Prostate, lung and colorectal remain the most common cancers among men; while breast, colorectal and lung cancers are the most common cancers among women.
In recent years, there have been significant gains in the management of these conditions. At least one of the success stories in the clinical management of a cancer is the early diagnosis and treatment options now available for primary breast cancer. The other is employment of effective and nontoxic anti-estrogen agents that block the actions of estrogen either at its receptor sites or at a point of its synthesis.
Obviously research on the function and activity of estrogen receptors, the structure and their function has been the subject of many recent investigations. Estrogen receptors belong to a large family of structurally related ligand-inducible transcription factors, including steroid receptors, thyroid/retinoid receptors, vitamin D receptors known as nuclear receptors. While the true ligand for nuclear receptors have not been described, there are distinct small molecules that are able to bind to such receptors and trigger a cellular response.
Estrogens and estrogen receptor modulators bind to estrogen receptors, classified into two types; α and β, to form discrete molecular complexes that exert pleiotropic tissue-specific effects by modulating the expression of target genes. The ligand-bound estrogen receptor acts as a key transcription factor in various molecular pathways, and modulation of ER expression levels is important in determining cellular growth potential.
While both these types of receptors bind to estrogen, as well as other agonists and antagonists, the two receptors have distinctly different localization concentration within the body. Aside from some structural differences between the α and β types, when complexes with estrogen, the two were shown to signal in opposite way, with estrogen activating transcription in the presence of Estrogen Receptor α (ERα) and inhibiting transcription in the presence of Estrogen Receptor β (ERβ).
Tamoxifen is primarily one of the first selective estrogen receptor modulators that have become first-line therapy for hormonal treatment of breast cancer, both for adjuvant treatment and for therapy of metastatic disease. Tamoxifen is a competitive inhibitor of estradiol binding to the estrogen receptor inhibiting its estrogen binding to the estrogen binding element on DNA. It has been suggested that Tamoxifen's binding to the estrogen receptors significantly alters the structural configuration of the estrogen receptors, rendering the binding sites dysfunctional towards any endogenous estrogen. Such structural deformation of the receptor could explain the profound side effect profile associated with the use of Tamoxifen.
At least another shortcoming of Tamoxifen is its ineffectiveness against non-estrogen-dependent tumors and lower efficacy in pre-menopausal women. Additionally, Tamoxifen undergoes an isomerization under physiological conditions from a therapeutically useful antiestrogenic compound to an estrogenic isomer which can stimulate the growth of estrogen-dependent tumor cells, providing an undesired clinical outcome, particularly among patients suffering from estrogen dependent tumors.
U.S. Pat. No. 4,732,904 discloses other type of estrogen receptor antagonists conventionally known as hydrazone compounds. It is thought that these antiestrogenic hydrazone compounds do not undergo isomerization to estrogenic compounds under physiological conditions and the estrogenic side effects observed for Tamoxifen are therefore absent. These hydrazone compounds have been proposed as alternative treatments for estrogen-dependent breast cancers. Among these, the substituted benzophenone nitrophenyl hydrazones, such as 4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone are described to be superior.
The complex of the receptor and the antiestrogen such as hydrazone based compounds or Tamoxifen may then bind to nuclear chromatin in an atypical manner for a longer time than the normal hormone receptor complex. Antiestrogens may also be able to deplete the cytoplasm of free receptor. Either or both of these effects could severely impair the continued growth of an estrogen-dependent tumor.
There has also been an increased interest in the use of aromatase inhibitors to block specifically the local production of estrogens that may contribute substantially to hormone responsive disease such as breast cancer. Aromatase (CYP19) is described as the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. Estrogen deprivation through aromatase inhibition is described as an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.
Exemestane (which is sold as Aromasin, is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione) and acts as an irreversible, steroidal aromatase inactivator. It is believed to act as a false substrate for the aromatase enzyme, and processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation. U.S. Pat. Nos. 4,808,616, and 4,904,650, the teachings of which are incorporated herein in their entirety, disclose 6-alkylidenandrosta-1,4-diene-3,17-dione derivatives, such as exemestane, and methods of making them. U.S. Pat. No. 4,876,045 discloses a method of preparing 6-methylene derivatives of androsta-1,4-diene-3,17-diones. U.S. Pat. No. 4,990,635 discloses a process for making 6-methylene derivatives of androsta-1,4-diene-3,17-diones.
The preparation of intermediates that may be useful in preparing exemestane is disclosed in U.S. Pat. No. 3,274,176. In German patent DD 258820, 6-hydroxymethyl-androsta-1,4-diene-3,17-dione is prepared from androsta-1,4-diene-3,17-dione via 1,3-dipyrrolidinoandrosta-3,5-dien-17-one.
Co-pending international application no. PCT/US2005/001248 filed Jan. 14, 2005 (PCT Publication Number WO 2005/070951), incorporated herein by reference in its entirety, also describes the preparation of intermediates that are useful in preparing exemestane. The structure of Exemestane is shown below.

Schneider et. al, in “Course of the reaction of steroidal 3,5-dienamines with formaldehyde”, Helvetica Chimica Acta (1973), 56(7), 2396-2404, discloses the following compounds:
where the  symbol represents a double bond, it means a keto group and no R6 is present; and where the  symbol represents a single bond R6 is hydrogen (i.e. an alcohol group). Unlike the compounds of the present invention, Schneider's compounds do not embrace estradiol, testostrone or dihydrotestostrone variations.
A tri-hydroxyl substituted derivative of estranes is disclosed in U.S. Pat. No. 3,377,363 to Tadanier et. al, and the 3 hydroxy substituent on the aromatic ring of the present compounds is not disclosed.
U.S. Pat. No. 5,914,324 to De Funari et. al, discloses 6-hydroxy and oxy androstane derivatives for hypertension and heart failure. U.S. Pat. No. 6,384,250 to Gobbini, et al., discloses the hydroxyl and ketone substituents at the 6 position in the preparation of (E,Z) 3-(2-aminoethoxyimino)-androstane-6,17-dione. These compounds were directed towards the treatment of heart failure. The effects of alkyl hydroxyl substitution at the 6 position is not disclosed.
Tanenbaum, et. al, “Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains”, Proc. Natl. Acad. Sci. USA, Biochemistry, Vol. 95,pp 5998-6003, discloses the mechanism of ER receptors and notes that estradiol containing an aromatic ring with a 3-hydroxy substituent binds well with the ER ligand binding region. It is disclosed that a flat aromatic group without the 19 methyl substituent is favored.
U.S. Pat. No. 5,892,069 to D'Amato describes estradiol derivatives that inhibit tubulin polymerization during cell mitosis. Given the above, a need still exists to identify new and effective agents for treating cancer.
Another point of concern in the field is the eventual conversion of some estrogen-dependent cancers, i.e. breast cancer, to estrogen-independent types. This may be accounted for by a natural loss of differentiation by the tumor cells. Estrogen-dependent cancer cells have often been observed to eventually lose their ability to produce estrogen-binding protein receptors and degenerate into much more aggressive estrogen-independent life-threatening cancers. Indeed, the use of antiestrogens to treat estrogen-dependent tumors may lead to the clonal selection of estrogen-independent tumor cells and therefore may promote the conversion of an estrogen-dependent cancer to a non-estrogen-dependent cancer.
Cancers of other organs, such as lung and colon, may not concern estrogen-binding protein receptors and thus are considered independent of estrogens for cell replication. Such estrogen-independent tumors are not as susceptible to the antiestrogenic properties of drugs such as Tamoxifen, aromatase inhibitors. Thus other chemotherapeutic agents must be used to treat such tumors. Many compounds have been documented to be effective to varying degrees against estrogen-independent tumors.
These compounds are reviewed in many references and typically administered in combination regimen chemotherapy causing substantial side effect to the patients. The underlying principle of using general cytotoxic agents in chemotherapy is based upon the observation that malignant tumor cells replicate at a higher rate than normal body cells and are therefore correspondingly more susceptible to these compounds. Similarly, normal tissues that proliferate rapidly (for example, bone marrow and intestinal epithelium) are subject to substantial damage once exposed to these potent cytotoxic drugs, and such toxicity often limits utility.
On the other hand, slow growing tumors with a small growth fraction, for example carcinomas of the colon or lung, are often unresponsive to cytotoxic drugs. Aside from the treatment of estrogen-dependent and estrogen-independent tumors, many of the cytotoxic drugs are currently being used for other proliferative diseases with rapidly growing cells involved non-cancerous or non-malignant hyperproliferative conditions.
Also the increasing importance of effective therapeutic management of viral diseases such as AIDS, herpes, various types of hepatitis and bacterial infections, especially among immune suppressed patients, calls for alternative modes of therapy with favorable side effect profile.
Accordingly, there is not only a need for new and improved cancer chemotherapeutics that can be used to treat both estrogen-dependent and estrogen-independent tumors with minimal risk of systemic toxicity challenging the quality of life for such fragile population of patients, but also for therapeutic remedies that target non-cancerous hyperproliferative conditions which can benefit from effective doses of estradiol derivatives. The hyperproliferative cells can be normal, rapidly growing cells or abnormal cells and can include tissue having rapidly growing endogenous cells or their abnormal subpopulation, or other tissues generally exogenous to the patient.
None of the teachings of prior art provide for a therapeutic estradiol derivative with favorable side effect profile that can be used for these types of conditions.